Bacteria are highly varied, and have developed mechanisms to diversify to enable survival in a dynamic world. Bacteria that are obligate colonizers of specific hosts have additional benefits and challenges compared with those with broader host ranges or those that are free-living. Helicobacter pylori is a gram negative bacterium that colonizes the human stomach. Once acquired, H. pylori persists in its host essentially for life (in the absence of antimicrobial therapy), is intimately related to human gastric tissues, including injection of H pylori constituents into epithelial cells, and when present, is the single dominant microbe in the human stomach. In addition to its major medical importance, H. pylori also is a model system for understanding microbial persistence in a host and the enabling mechanisms. Our hypothesis is that H. pylori evolved specific genetic mechanisms to create and control variation that maximizes its persistence in the gastric niche. We will address this hypothesis, through several Specific Aims: In Aim 1, we will assess how H. pylori controls intragenomic variation involving short sequence repeats (SSRs), using DNA repair and recombination genes. We plan to examine this question under steady state and fluctuating environments in vitro, and employ mathematical models to understand the underlying principles of the dynamics. In Aim 2, we will assess how H. pylori controls susceptibility to transforming DNA, and then determine its costs and benefits in vivo, in a murine model. Finally, in Aim 3, we plan to conduct experiments to understand the spatial localization (biogeography) of H. pylori colonization; to determine whether there is heterogeneity of sectoring of H. pylori strains in the gastric environment, under fixed or oscillating conditions. For each of the experiments to be performed, we will develop mathematical analyses to find the general properties under which the microbial populations diversify and are selected. Through such analyses, we hope to create the basis for a deeper understanding of how microbes are able to persist for long periods in their human hosts. PUBLIC HEALTH RELEVANCE: Helicobacter pylori is a bacterium that lives in the human stomach and that is extremely common, and as with other microbes that reside in the human body, it may cause disease (such as ulcers or stomach cancer), but also may provide benefits to its hosts. We have been studying the mechanisms that H. pylori use to change themselves, through mutation, and how these changes affect the interactions with human cells and tissues. Including mathematical analyses in these studies also permits a generalization of the principles and their applications to other microbes involved in human health and disease.